Diacyloxy-benzoic acid anilides

ABSTRACT

DIACYLOXY-BENZOIC ACID ANILIDES OF THE GENERAL FORMULA   1-((R1-PHENYL)-NH-CO-),2,6-DI(R2-COO-),3-X,5-(O2N-)BENZENE   IN WHICH X REPRESENTS HYDROGEN OR HALOGEN, R1 REPRESENTS 1 TO 3 NITRO GROUPS, TRIFLUOROMETHYL GROUPS AND/OR HYDROGEN; LOWER ALKYL WHICH MAY BE SUBR2 REPRESENTS HYDROGEN; LOWER ALKYL WHICH MAE SUBSTITUTED BY HALOGEN, LOWER ALKOXY OR PHENYL; ALKENYL HAVING 3 TO 6 CARBON ATOMS; CYCLOALKYL HAVING 4 TO 6 CARBON ATOMS; PHENYL; AN UNSATURATED HETEROCYCLIC 5OR 6-MEMBERED RING; ALKYL-AMINO OR DIALKYL-AMINO IN WHICH THE ALKYL GROUPS EACH CONTAIN 1 TO 4 CARBON ATOMS OR MAY FORM TOGETHER WITH THE NITROGEN ATOM A PYRROLIDINE, PIPERIDINE, MORPHOLINE OR N-METHYL-PIPERAZINE RING.

United States Patent 3,792,054 DIACYLOXY-BENZOIC ACID ANILIDES HeinrichRushig, Bad Soden, Taunus, Dieter Duwel, Hofheim, Taunus, and JohannKonig, Niederhofheim, Taunus, Germany, assignors to Farbwerke HoechstAktiengesellschaft vormals Meister Lucius 8: Bruniug, Frankfurt am Main,Germany No Drawing. Original application June 5, 1970, Ser. No. 43,949.Divided and this application May 31, 1972, Ser. No. 258,431 Claimspriority, application Germany, June 9, 1969, P 19 29 150.0 Int. Cl.(107d 29/30 US. Cl. 260-29354 Claims ABSTRACT OF THE DISCLOSUREDiacyloxy-benzoic acid anilides of the general formula in which This isa division of application Ser. No. 43,949 filed June 5, 1970.

The present invention provides diacyloxy-benzoic acid anilides of thegeneral formula in which X represents hydrogen or halogen,

R represents 1 to 3 nitro groups, trifluoromethyl groups and/or halogenatoms,

R represents hydrogen; lower alkyl which may be substituted by halogen,lower alkoxy or phenyl; alkenyl having 3 to 6 carbon atoms; cycloalkylhaving 4 to 6 carbon atoms; phenyl; an unsaturated heterocyclic 5- or6-membered ring; alkylamino or dialkyl-amino in which the alkyl groupseach contain 1 to 4 carbon atoms or may form together with the nitrogenatom a pyrrolidine, piperidine, morpholine or N-methyl-piperazine ring.

The invention furthermore provides a process for preparing theabove-specified compounds, wherein dihydroxybenzoic acid anilides of thegeneral formula N02 OH in which X and R have the meanings given above,are acylated.

3,792,054 Patented Feb. 12, 1974 "Ice For this reaction, there may beused as starting material for example the following dihydroxy-benzoicacid anilides: 3-nitro-2,6-dihydroxy-benzoic acid-4-chloroanilide,3-nitro-2,6-dihydroxy-benzoic acid-4'-bromoanilide,3-nitro-2,6-dihydroxy-benzoic acid4'-iodoanilide,3-nitro-2,6-dihydroxy-benzoic acid-2,4'-dichloroanilide,3-nitro-2,6-dihydroxy-benzoic acid-3',4'-dichloroanilide,3-nitro-2,6-dihydroxy-benzoic acid-2,6'-dichloroanilide,3-nitro-2,6-dihydroxy-benzoic acid-2',5-dichlor0anilide, 3-nitro-2,6-dihydroxy-benzoic acid-2',4,6'-tri-chloroanilide,3-nitro-2,6-dihydroxy-benzoic anilide,

3nitro-2,6-dihydroxy-benzoic acid- '-tri-fluoromethylanilide,

3-nitro-2,G-dihydroxy-benzoic acid-3',5'-bis-trifluoromethylanilide,

5-chloro-3-nitro-2,6-dihydroXy-benzoicacid-3',5-bis-trifluoromethylanilide,

5-bromo-3-nitro-2,G-dihydroxy-benzoicacid-3',5-bis-trifluoromethylanilide,

5-iodo-3-nitro-2,6-dihydroxy-benzoicacid-3',5-bis-trifluoro-methylanilide.

These compounds may be prepared for example by the reaction ofcorresponding X-substituted 3-nitro-2,-6-dihydroxy-benzoic acid esterswith R -substituted anilines.

The acylation of the two phenolic hydroxyl groups is effected in knownmanner by the action of acylating agents. For this purpose, carboxylicacids or their reactive derivatives, for example acid anhydrides, acidhalides, especially acid chlorides, as well as reactive derivatives ofcarbamic acid and isocyanates are suitable. For example, theabove-mentioned derivatives of the following carboxylic acids may beused: acetic acid, propionic acid, butyric acid, isobutyric acid,valeric acid, caproic acid, B-chloropropionic acid, ,B,a-dichlorobutyricacid, B-methoxy-propionic acid, phenylacetic acid, phenylpropionic acid,(itpehnyl-isobutyric acid, acrylic acid, crotonic acid, 2-hexenic acid,cyclopentanoic acid, cyclohexanoic acid, benzoic acid,2-thiophen-carboxylic acid, pyrrol-2-carboxylic acid, pyromucic acid,picolinic acid, nicotinic acid, thiaz0l-4- carboxylic acid.

-For reacting the starting materials, the reaction components may beallowed to react directly with one another. In order to facilitate theacylation it is often of advantage to add a basic or acidic condensationagent. Suitable basic compounds are, for example tertiary amines such aspyridine or triethylamine. As acidic condensation agents, for examplesulfuric acid, sulfonic acids, polyphosphoric acids or anhydrous zincchloride may be used. Furthermore, it is of advantage to carry out thereaction of the dihydroxybenzoic acid anilides in the presence of asolvent or diluent. For this purpose, inert polar or non-polar solventssuch as benzene, toluene, chlorobenzene, methylene chloride, chloroform,acetone, dibutyl ether, tetrahydrofurane, dioxane, dimethylformamide ortetramethylene-sulfone may be used. If the acylating agent used is aliquid, it may be employed in excess and therewith serve as a diluent.The same applies to condensation agents, for example pyridine.

The acylation reaction takes place at room temperature or at slightlyelevated temperatures. In general, the boiling temperature of thesolvent used is not to be exceeded. In most cases, the reaction iscomplete after a few hours. The products of the invention can beisolated, for example by removing the diluent by distillation or by theaddition of water and following crystallization from a suitable solvent.

The novel diacyloxy-benzoic acid anilides constitute, in general,crystalline colorless compounds which do not dissolve or dissolvesparingly only in water. They are distinguished by a marked anthelminticactivity. This activity is especially directed against liver flukes, inparticular against the great liver flukes Fasciola hepatica. Inpractice, the infestation of productive animals such as sheep and cattlewith liver flukes has considerable importance. In combating theseinfestations, the products of the invention have proved to be valuablechemo-therapeutic agents. They can be applied perorally orsubcutaneously, the mode of administration depending on the individualcase. The following table lists the doses of some products of theinvention whose single administration to naturally strongly infestedsheep resulted in complete cessation of the excretion of eggs and to acomplete liberation of the animals from liver flukes.

TABLE.CHEMOTHERAPEUTICAL TEST 15 111051;: sheep. Parasite: Fasciolahepatica] Therapeutic Mode dose of ad- (mgn/kg. minisbody Substancetration weight) 3-nitro-2, G-diacetoxy-benzoic acid-3, 6-bis-trlfiuoro-8.0. 2 methyl-anilide. R0. 8 3-nitr0-2, fi-dicapronyloxy-benzoicacid-3,5-bis-tri- 8.0. 5 fluoromethyl-anilide. P.o. 3-nitro-2,6di-(N-methyl-carbamyloxy)-benzoic S.c. 5

acid-3, 5-bis-trifiuoromethyl-anilide. P.o. 10 3-nitro-2, fi-bis-(N, N-diethyl-carbamyloxy) -benzoic P.0. 16

acid-3, 5-bis--triflnoromethyl-anilide. 5-iodo-3-nitro-2,G-diacetoxy-benzoic acid-4chloro- P.o. 5

anilide.

f N0rE.-P.o.=peroral administration. S.c.=subcutaneous admlnistraion.

The indicated doses were tolerated by the animals without side effects.

Hence, the novel compounds are valuable medicaments in veterinarymedicine for combating liver fluke infestations.

The following examples illustrate the invention:

EXAMPLE 1 3-nitro2,6-diacetoxy-benzoic acid-4'-chloroanilide 15.5 g. of3-nitro-2,6-dihydroxy-benzoic acid-4'-chloroanilide, 40 ml. ofacetanhydride and 3 drops of concentrated H 50 were heated together for70 minutes to 85 C. After cooling, 120 ml. of water were added, thecrystals that had precipitated were filtered off with suction, washedwith 50 ml. of water, dried and recrystallized from benzene. 15.2 g. of3-nitro-2,6-diacetoxy-benzoic acid-4'- chloroanilide, melting at 144 C.,were obtained.

EXAMPLE 2 (a) 3-nitro-2, 6-diacetoxy-benzoicacid-3',5'-bis-trifluoromethylanilide EXAMPLE 33-nitro-2,6-dicapronyloxy-benzoic acid-3',5'-bis-trifluoromethylanilide41 g. of 3-nitro-2,6-dihydroxy-benzoicacid-3',5'-bis-trifluoromethylanilide, 5 g. of anhydrous zinc chloride,150 ml. of benzene and 55 g. of caproic acid chloride were heatedtogether for 7 hours under reflux. The still hot solution was filteredand evaporated under reduced pressure. The residue was recrystallizedfrom the same volume of diisopropyl ether. 30 g. of3-nitro-2,6-dicapronyloxy-benzoic acid-3',5-bis-trifluoromethylanilidewere obtained. Melting point 95 C.

EXAMPLE 4 3-nitro-2,6-diacetoxy-benzoic acid-2,4',6'-trichloroanilide 95ml. of acetanhydride were added dropwise, while stirring, to a mixtureof 75 g. of 3-nitro-2,6-dihydroxybenzoic acid-2,4',6'-trichloroanilide,160 ml. of tetramethylene-sulfone and 15 g. of anhydrous zinc chloridein such a manner that the temperature did not exceed C. and the wholewas further stirred for 3 hours at 85 C. After cooling, 600 ml. of waterwere added, whereupon an oil precipitated which solidified after aboutone hour. The crude product was filtered oil with suction, washed with300 ml. of water and recrystallized from methanol. 46 g. of3-nitro-2,6-diacetoxy-benzoic acid-2',4,6'-trichloroanilide wereobtained. Melting point 191 C.

EXAMPLE 5 3-nitro-2,6-dibenzoy1oxy-benzoic acid-2',4,6-trichloroanilideml. of tetramethylene-sulfone, 30 ml. of pyridine and 38 g. of3-nitro-2,6-dihydroxy-benzoic acid 2',4',6'-trichloroanilide werestirred together at 50 C. 34 g. of ben'zoyl chloride were added dropwiseto the thus formed solution in such a manner that the temperature didnot exceed 70 C. and the Whole was further stirred for 2 hours at 50 C.After cooling, the whole was diluted with 450 ml. of water, the aqueoussolution Was decanted, boiled with 200 ml. of methanol and allowed tocrystallize. The crystals that had precipitated were filtered oif withsuction, washed with 50 ml. of methanol and recrys tallized frommethanol. 46 g. of 3-nitro-2,6-dibenzoyloxybenzoicacid-2',4,6-trichloroanilide were obtained. Melting point 197 C.(decomposition).

EXAMPLE 6 3-nitro-2,6-di-(N-methyl-carbamyloxy)-benzoic acid 3',5'-bis-trifluoromethylanilide 45 g. of 3-nitro-2,6-dihydroxy-benzoicacid-3',5-bistrifluoromethylanilide, 350 ml. of acetone, 0.5 ml. ofpyridine and 25 g. of methyl isocyanate were heated together for 10minutes to 40 C. A solution formed at first and later on crystallizationset in which was complete after 6 hours at room temperature. Thecrystals were filtered off with suction and washed with 80 ml. ofacetone. 36 g. of 3-nitro-2,6-di-(N-methylcarbamyloxy)- benzoicacid-3',5' bis trifluoromethylanilide were obtained. Melting point 226C. (decomposition).

EXAMPLE 7 3-nitro-2,6-bis- (N,N-diethyl-carbamyloxy) -benzoicacid-3',5'-bis-trifluoromethylanilide 45 g. of N,N-diethyl-carbamic acidchloride were added dropwise, while stirring, within 25 minutes, to 50g. of 3-nitro-2,6-dihydroxy-benzoic acid 3'5 bis trifluoromethylanilidein ml. ofpyridine. The whole was stirred for 30 minutes at roomtemperature and for 3 hours at 70 C. After cooling, it was diluted with800 ml. of water, the solid product was filtered olf with suction,washed with ml. of water and after drying, it was recrystallized fromdiisopropyl ether. 45 g. of3-nitro-2,6-bis-(N,N-diethyl-carbamyloxy)-benzoicacid-3',5'-bis-trifluoromethylanilide were obtained. Melting point139141 C.

EXAMPLE 8 5-iodo-3-nitro-2,6-diacetoxy-benzoic acid-4'-chloroanilide (a)30.8 g. of 3-nitro-2,6-dihydroxy benzoic acid 4- chloroanilide, 230 ml.of glacial acetic acid and 16.2 g.

, utes to 85 C. After cooling, the almost colorless crystals werefiltered off with suction and washed with 8 m1. of methanol. 7.5 g. of5-iodo-3-nitro-2,6 diacetoxy benzoic acid-4'-chloroanilide wereobtained. Melting point 201 C.

EXAMPLE 9 3-nitro'2,6-bis-(furoyloxy)-benzoic acid-4-bromoanilide 30 g.of furane-Z-carboxylic acid chloride were added dropwise within 20minutes, while stirring, to a mixture of 25 g. of3-nitro-2,6-dihydroxy-benzoic acid-4-bromoanilide, 70 ml. oftetramethylene-sulfone and 30 ml. of pyridine in such a manner that thetemperature did not exceed 40 C. The whole was stirred for 2 hours atroom temperature, diluted with 400 ml. of water, the aqueous solutionwas decanted and the oil that remained behind was stirred for 1 hourwith 120 ml. of methanol, whereupon crystallization took place. Thecrystals were filtered otf with suction and washed with 45 ml. ofmethanol. 30 g. of 3-nitro-2,-6-bis-(furoyloxy)-benzoic acid-4'bromoanilide were obtained. Melting point. 191 C.

EXAMPLE (a) 3-nitro-2,-6-bis- (piperidino-carbonyloxy) -benzoicacid-3',5'-bis-trifiuoromethylanilide 49 g of piperidino-N-carboxylicacid chloride were added dropwise, while stirring, to 50 g. of3-nitro-2,6- dihydroxy-benzoic acid-3',5'-bis-trifluoromethylanilide in135 m1. of pyridine in such a manner that the temperature was maintainedbetween 40 and 45 C. The whole was then stirred for 2 hours at 70 C.,cooled, diluted with 750 ml. of water and the aqueous solution wasdecanted. The oil that remained behind was diluted with 100 ml. ofethanol and allowed to crystallize. The crystals were filtered off withsuction and washed with 60 ml. of ethanol. 50 g. of3-nitro-2,6-bis-(piperidino-carbonyloxy)- benzoic acid 3',5' bistrifluoromethylanilide were obtained. Melting point 166 C.

In analogous manner there were obtained:

(b) 3-nitro-2,fi-dibutyryloxy-benzoicacid-3',5-bistrifluoromethylanilide.

(c) 3-nitro-2,6-bis-cyclohexyloxy-benzoicacid-3',5'-bistrifluorornethylanilide.

(e) 3-nitro-2,6-bis-pyrrolidino-carboxyloxy-benzoic acid-3',5'-bis-trifluoromethylanilide.

We claim: 1. A diacyloxy-benzoic acid anilide of the formula wherein Xis hydrogen or halogen; R is 1 to 3 members selected from the groupconsisting of trifluoromethyl and halogen; and R is alkylamino ordialkylamino in which the alkyl groups each have from 1 to 4 carbonatoms, pyrrolidino, piperidino, morpholino, or N-Inethyl piperazmo.

2. 3-nitro-2,'6-di-(N-methylcarbamyloxy)-benzoic acid-3',5-bis-trifluoromethylanilide.

3. 3-nitro-2,6-bis-(N,N diethylcarbamyloxy) benzoicacid-3',5'-bis-trifiuoromethylanilide.

4. 3-nitro-2,6-bis-(piperidinocarbonyloxy)-benzoic acid3',5-bistrifluoromethylanilide.

5. 3-nitro-2,6-bis-pyrrolidinocarbonyloxy-benzoic acid-3,5-bis-trifiuoromethylanilide.

References Cited Christ et al.: Berlin. Miinchen Tierarztl. Wochenschr.1970, 83(4), 61-5; Chem. Abstracts 73:12880g (1970).

Pfeiffer: Deut. Tierarztl Wochenschr. 1970, 77(5), 104-7; Chem.Abstracts 73:129196 (1970).

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner U.S. Cl.X.R.

260-246 B, 268 C, 295 AM, 295.5 A, 302 H, 332.2 C, 326.3, 347.5, 468 R,476 R, 479 R, 479 C, 479 S, 559 S; 424-248, 250, 263, 266, 267, 270,274, 275, 285, 299. 300, 308, 311, 314

